A chelator or chelating agent is a polydentate ligand that bonds to more than one coordination site of a metal ion. Chelating agents have long been known in the art to be useful in chemical analysis, in environmental remediation and in medicine. In chelation therapy, a chelating agent is employed to bind a poisonous metal agent such as mercury, arsenic, iron, lead or aluminum in order to displace the ion from biological ligands such as proteins and convert the metal ion into a less toxic form that can be excreted without further interaction with the body.
The present invention relates to (1) novel chelating agents or compounds, (2) novel immobilized, tethered chelators comprising the novel chelating compounds linked to immobilized supports and (3) methods of employing the novel compounds and chelators to remove trivalent and tetravalent metal ion such as Al3+ and Pu4+ from aqueous systems in situ, in vivo and in vitro.
There have been previous studies of tripodal, trihydroxamic acids. Most of these ligands are based on tripodal platforms of tris(2-aminethyl)amine (tren) (Matsumoto et al., Chem. Commun. 2001, 978-979; Matsumoto et al., Inorg. Chem., 2001, 40: 190-191; Matsumoto et al., Inorg. Chem. 2004, 43: 8538-8546; Ng et al., Inorg. Chem. 1989, 28: 2062-2066), tris(3-aminopropyl)amine (Matsumoto et al., Eur. J. Inorg. Chem. 2001, 2481-2484); or nitrilotriacetic acid (nta) (Lee et al, J. Med. Chem. 1985, 28: 317-323; Hara et al., Inorg. Chem. 2000, 39: 5074-5082). These studies teach that such ligands form Fe3+ complexes with binding constants in the range of 1028 to 1033, so long as there are five or six atoms connecting the bridgehead atom of the platform and the first atom of the hydroxamate functional group on the sidearm (Matsumoto et al., Eur. J. Inorg. Chem. 2001, 2481-2484; Matsumoto et al., Inorg. Chem. 2001, 40: 190-191; Ng et al., Inorg. Chem. 1989, 28: 2062-2066). These ligands include amide functional groups in the sidearms, and the iron complexes appear to be stabilized by intramolecular hydrogen bonding between the amide functional groups (Matsumoto et al., Inorg. Chem. 2001, 40:190-191).
The common feature of all the above ligands is that the bridgehead atom is a tertiary nitrogen. To attach these ligands to a solid support via this nitrogen would require the formation of a quaternary ammonium group. This is expected to have an adverse effect on the chelating ability of the ligand. It will introduce a permanent positive charge on the ligand, resulting in electrostatic repulsion of the target metal ion. In some cases, it will also require a change in the conformation of the metal complex.
A few tripodal tris(hydroxamate) ligands have been prepared in which the bridgehead atom is a carbon, rather than a nitrogen. These ligands are built on tripodal bases of either 1,1,1-tris(hydroxymethyl)ethane (Motekaitis et al., Inorg. Chem. 1991, 30: 1554-1556) or 1,1,1-tris(hydroxymethyl)propane (Dayan et al., Inorg. Chem. 1993, 32: 1467-1475). Hydroxamate groups were added to these tripodal bases through ether linkages. These studies teach that one needs 4 or 5 atoms between the bridgehead carbon and the first atom of the hydroxamate functional group for strong metal binding. The Fe3+ complexes of these ligands have binding constants of 1026 to 1028. However, it is not possible to link these ligands to a polymeric support through the quaternary carbon bridgehead atom.
The current invention is based in the use of hydroxyalkylaminomethanes, especially the common buffer tris(1,1,1-tris(hydroxymethyl)aminomethane), as the tripodal base. The use of hydroxylalkylaminomethanes allows us to construct tripodal chelating functional groups that will mimic the high metal binding affinities of the ligands already in the literature, but it also provides a free amine group that can be used to easily attach the ligands to a variety of solid supports.
In issued U.S. Pat. No. 7,932,326, all of the hydroxamate ligands are derived from tris[tris(hydroxymethyl)aminomethane]. The oxygen atoms of tris are alkylated with alkyl groups of various lengths terminating in hydroxamic acids. The amine of the tris is linked to a polymer support via sulfonamide, carboxamide or urea groups amongst others, to give the resin supported ligands. This document relates to an extension of that work.